The goal of this project is to enhance the limited knowledge about a new generation of optimized gold nanorod-assisted photothermal therapy (Au NR PTT) for the evaluation of toxicity using animal models and xenografted tumor ablation with low doses of NIR light. These gold nanorods exhibit higher intrinsic absorption efficiencies leading to faster and higher heating effects than the prototypical gold nanoshells or nanocages (Au NSs / Au NCs). Their biodistribution, acute and long-term toxicity, and tumor uptake will be further explored, as well as how their properties are influenced by tuning the particle aspect ratio (length/width), their surface coating, and especially the conjugation of tumor targeting ligands. A thorough comparison of the toxicity, biodistribution and efficacy of Au NRs with nanospheres (NSs) and other NIR-absorbing nanoparticles, such as nanocages (NCs), is critical to the development of safer and more effective PTT. From this research the best NlR-absorbing Au NPs will be formulated along with the best treatment methodology to produce the most effective and least toxic gold nanoparticle for photothermal therapy of cancer. To this end the effects of particle size, surface coating and tumor targeting ligands on the biodistribution and toxicity of Au NR model systems will be investigated due to their great potential to become the most effective PTT. This will be optimized for the treatment of head and neck cancer using comparative efficacy studies on three nanogold subtypes incorporating a variety of important factors - such as nanoparticle delivery and laser treatment strategy. Preclinical pharmacokinetic, pharmacodynamic and toxicology studies will be carried out towards the end of the project period in order to validate the optimized Au NPs. Through the highly integrated team effort involving research nanotechnology engineers, chemists, biologists, and physician/scientists (oncologists) at Emory University and the Georgia Institute of Technology, it will be possible to overcome the problems inherent in the treatment of cancer with conventional photothermal therapy by developing gold nanotechnology-driven PTT that is both safe and effective, to be further developed into future clinical trials. RELEVANCE (See instructions): Successful development of gold-nanorod assisted photothermal therapy is an important treatment modality for locally advanced or recurrent head and neck cancer in patients who failed standard approaches including surgery, radiation, and/or chemotherapy. Patients with locally invasive unresectable and refractory to chemotherapy and radiation therapy have very limited options remaining and will eventually die from this disease. This Au NR PTT has a great therapeutic potential to target locally advanced disease which has become resistant to conventional and standard treatment.